Rosy Reynolds

Non-susceptibility trends among staphylococci from bacteraemias in the UK and Ireland, 2001-06

OBJECTIVES Investigation of the antibiotic susceptibilities and trends for staphylococci collected from bacteraemia cases in the UK and Ireland, from 2001 to 2006, as part of the British Society for Antimicrobial Chemotherapys Bacteraemia Surveillance Programme. METHODS Twenty-five hospitals from the UK and Ireland each collected up to 10 consecutive isolates of both Staphylococcus aureus and coagulase-negative staphylococci (CoNS) per year from 2001 to 2006. MIC determination and identification to species level were carried out centrally. mecA and also mupA alleles were sought by PCR in S. aureus and CoNS from 2005 and 2006, respectively. RESULTS One thousand four hundred and forty-eight S. aureus and 1214 CoNS were collected. The overall prevalence of methicillin resistance was 42% (with </=6% annual fluctuation) for S. aureus and 67% (range 54% to 80%) for CoNS. Resistance to aminoglycosides, macrolides, quinolones and tetracyclines was strongly associated with methicillin resistance in both species groups. Many (20.8%) CoNS and three (0.2%) S. aureus isolates were non-susceptible to teicoplanin, but there was no vancomycin non-susceptibility found in S. aureus and only one vancomycin-intermediate CoNS isolate. There was little evidence of susceptibility trends over time for any antibiotic, with the surveillance period preceding the recent fall in methicillin-resistant S. aureus (MRSA) prevalence indicated by the mandatory surveillance of MRSA bacteraemia in England. The newer antibiotics, ceftobiprole, daptomycin, linezolid, telavancin and tigecycline, all had excellent activity against staphylococci. CONCLUSIONS Multiresistant staphylococci remain abundant in the UK and Ireland but many new antimicrobials are becoming available and these may prove effective alternatives to glycopeptides.

Non-susceptibility trends among Enterobacteriaceae from bacteraemias in the UK and Ireland, 2001–06

BACKGROUND Enterobacteriaceae are common agents of bacteraemia, with Escherichia coli accounting for 20% of the cases. Reflecting this importance, members of the family constitute 4 of the 12 collection groups in the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme. METHODS MICs from the BSAC surveillance programme were reviewed, along with bacteraemia reports received by the Health Protection Agency (HPA) via its CoSurv/LabBase system. Isolates with unusual resistances were subjected to molecular analysis. RESULTS The BSAC and HPA systems both revealed dramatically increasing resistance to cephalosporins, ciprofloxacin and gentamicin among E. coli and Klebsiella spp., with cephalosporin resistance largely contingent on the spread of CTX-M extended-spectrum beta-lactamases (ESBLs); fluoroquinolone resistance also increased among Proteus mirabilis and ESBL-negative E. coli. Carbapenem resistance remained extremely rare, but two Enterobacter spp., from the same patient in different years, had KPC carbapenemases, while a few isolates had carbapenem resistance contingent upon combinations of beta-lactamase and impermeability, and ertapenem MICs for AmpC-derepressed Enterobacter spp. rose over time. Three new agents-ceftobiprole, doripenem and tigecycline-were tested. Ceftobiprole was broadly active, except against ESBL producers and Klebsiella oxytoca hyperproducing K1 enzyme, and was variable against AmpC-derepressed Enterobacter spp. and against Proteus vulgaris. Doripenem was more potent than imipenem. Tigecycline was almost universally active against E. coli, but low-level non-susceptibility (MIC 2 mg/L) was frequent among Klebsiella spp. CONCLUSIONS E. coli and Klebsiella spp. showed dramatic shifts, with sharply rising non-susceptibility to cephalosporins, ciprofloxacin and gentamicin. The rise in cephalosporin resistance reflected dissemination of CTX-M ESBLs. Carbapenems remain broadly active and new agents offer potential.

Declining cephalosporin and fluoroquinolone non-susceptibility among bloodstream Enterobacteriaceae from the UK: links to prescribing change?

OBJECTIVES The UK saw major increases in cephalosporin and quinolone resistance amongst Enterobacteriaceae from 2001 to 2006, with cephalosporin resistance largely reflecting dissemination of CTX-M extended-spectrum β-lactamases (ESBLs). We review subsequent trends. METHODS Data were extracted from Public Health Englands national database (LabBase), which collects susceptibility results for bloodstream isolates from hospital microbiology laboratories in England, Wales and Northern Ireland, and from the BSAC Bacteraemia Resistance Surveillance System, which centrally tests bloodstream isolates from 25-40 sentinel UK and Irish laboratories. Reference laboratory submissions were also reviewed. RESULTS LabBase and BSAC data showed that rates of non-susceptibility to cephalosporins and quinolones rose amongst Escherichia coli and Klebsiella spp. until mid-decade (2004-07) before plateauing or falling; similar falls in non-susceptibility began slightly earlier in Enterobacter spp. These reversals in trend occurred whilst the incidence of E. coli bacteraemias was rising, the incidence of Klebsiella bacteraemias was stable and the incidence of Enterobacter bacteraemias was falling; they were not paralleled in EARS-Net data for continental Europe and did not reflect the displacement of single mechanisms. They coincided with large reductions in hospital cephalosporin and quinolone use, owing to concern about Clostridium difficile, with replacement by penicillin/β-lactamase inhibitor combinations, which have borderline activity against ESBL producers, but consistently lack activity against carbapenemase producers. CONCLUSIONS Non-susceptibility to cephalosporins and quinolones has declined among bloodstream Enterobacteriaceae in the UK, probably reflecting prescribing shifts. The penicillin/β-lactamase inhibitor combinations that have largely replaced cephalosporins and quinolones may add to selection for carbapenemase producers.

Non-susceptibility trends among enterococci and non-pneumococcal streptococci from bacteraemias in the UK and Ireland, 2001–06

OBJECTIVES To describe the current patterns and trends in antimicrobial susceptibility in enterococci and streptococci (excepting pneumococci) from bacteraemia in the UK and Ireland from 2001 to 2006. METHODS In each year 2001-06, blood culture isolates were collected by 25 laboratories distributed across the UK and Ireland. In total, there were 1408 isolates of enterococci, 1332 of beta-haemolytic streptococci and 1012 of alpha- and non-haemolytic streptococci. A single central laboratory re-identified the isolates and measured MICs by the BSAC agar dilution method. RESULTS The prevalence of reduced susceptibility in streptococci and enterococci did not change significantly for most antibiotics, but trends were noted to increased ampicillin, imipenem and vancomycin resistance in Enterococcus faecium. The prevalence of reduced susceptibility to macrolides and tetracycline in streptococci, to tetracycline and gentamicin (high level) in enterococci and to beta-lactams and glycopeptides in E. faecium were all high, with some differences in the prevalence among species or groups. CONCLUSIONS Reduced susceptibility to some antimicrobial agents among streptococci and enterococci remains common and continued surveillance is warranted.

Rapid Identification of Major Escherichia coli Sequence Types Causing Urinary Tract and Bloodstream Infections

ABSTRACT Escherichia coli sequence types (STs) 69, 73, 95, and 131 are collectively responsible for a large proportion of E. coli urinary tract and bloodstream infections, and they differ markedly in their antibiotic susceptibilities. Here, we describe a novel PCR method to rapidly detect and distinguish these lineages. Three hundred eighteen published E. coli genomes were compared in order to identify signature sequences unique to each of the four major STs. The specificities of these sequences were assessed in silico by seeking them in an additional 98 genomes. A PCR assay was designed to amplify size-distinguishable fragments unique to the four lineages and was validated using 515 E. coli isolates of known STs. Genome comparisons identified 22 regions ranging in size from 335 bp to 26.5 kb that are unique to one or more of the four predominant E. coli STs, with two to 10 specific regions per ST. These regions predominantly harbor genes encoding hypothetical proteins and are within or adjacent to prophage sequences. Most (13/22) were highly conserved (>96.5% identity) in the genomes of their respective ST. The new assay correctly identified all 142 representatives of the four major STs in the validation set (n = 515), with only two ST12 isolates misidentified as ST95. Compared with MLST, the assay has 100% sensitivity and 99.5% specificity. The rapid identification of major extraintestinal E. coli STs will benefit future epidemiological studies and could be developed to tailor antibiotic therapy to the different susceptibilities of these dominant lineages.

Non-susceptibility trends and serotype distributions among Streptococcus pneumoniae from community-acquired respiratory tract infections and from bacteraemias in the UK and Ireland, 1999 to 2007

OBJECTIVES Pneumococcal disease is prevalent and is a cause of significant morbidity and mortality in the UK and Ireland. We describe the antimicrobial susceptibility and serotype distributions of Streptococcus pneumoniae causing bacteraemia and community-acquired pneumonia in these countries from 1999/2000 to 2006/7, predominantly prior to the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) into the standard vaccination schedule in September 2006. METHODS The BSAC Respiratory and Bacteraemia Resistance Surveillance Programmes collected S. pneumoniae from sentinel laboratories distributed across the UK and Ireland. A central laboratory for each programme re-identified the isolates, determined their serotypes and measured MICs by the BSAC agar dilution method. RESULTS The prevalence of antimicrobial non-susceptibility, although significant, was generally below the global average. There was no convincing evidence of increasing non-susceptibility over time in either study. The results showed clear differences in the serotype distribution between respiratory and blood isolates, but suggested that PCV7 would provide adequate coverage of invasive isolates in the UK and Ireland. A significant and rapid increase of the non-vaccine serotype 1 among blood isolates from 2001 to 2006 was worrying, given the spread of hypervirulent serotype 1 clones elsewhere in the world. CONCLUSIONS Continued surveillance of both antimicrobial non-susceptibility and serotype distribution changes following the introduction of PCV7 into the routine immunization schedule in the UK and Ireland is imperative. The data presented here, largely obtained prior to the introduction of PCV7 in the UK, provide a valuable baseline against which to monitor changes in antimicrobial non-susceptibility and serotype distribution and hence to identify the expansion of any significant clones.

Survey, laboratory and statistical methods for the BSAC Resistance Surveillance Programmes

OBJECTIVES The British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia and Respiratory Resistance Surveillance Programmes are designed for long-term surveillance of antimicrobial resistance in key pathogens of bloodstream and community-acquired respiratory infection in the UK and Ireland. This paper describes their methods in detail. METHODS Sentinel laboratories across the UK and Ireland contributed up to a fixed quota of isolates of defined bacterial groups. Collecting laboratories were compared with national benchmarks for size of Hospital Trust and distribution of bacteraemia pathogens. A central laboratory for each programme confirmed the identification of isolates, measured MICs by the BSAC agar dilution method and undertook further testing by standard methods. The variability of the MIC method was assessed by repeated annual testing of a panel of control isolates. Classification as susceptible, intermediate or resistant was by BSAC and European Committee on Antimicrobial Susceptibility Testing breakpoints. Statistical analysis was adjusted for inter-centre variation using random effects logistic regression. RESULTS Thirty-two laboratories contributed 16 550 respiratory isolates from 1999-2000 to 2006-07; 30 laboratories contributed 15 812 bacteraemia isolates from 2001 to 2006. Although large and teaching hospitals were over-represented, the pattern of bacteraemia organisms seen in the collecting laboratories in England and Wales was similar to that in national data reported to the Health Protection Agency. Replicate MIC measurements showed that >/=90% agreed within +/-1, and >/=98% within +/-2, doubling dilutions. CONCLUSIONS These surveillance programmes have provided reliable information on antimicrobial susceptibility in the UK and Ireland over six and eight seasons, respectively, so far. Detailed results showing non-susceptibility trends, and relationships with potential predictive factors, are presented in six linked papers in this Supplement.

Lack of upward creep of glycopeptide MICs for methicillin-resistant Staphylococcus aureus (MRSA) isolated in the UK and Ireland 2001–07

OBJECTIVES There have been several reports of upward creep in vancomycin MICs for Staphylococcus aureus [predominantly methicillin-resistant S. aureus (MRSA)] over recent years, but only in single centres or using contemporaneous results. We aimed to test the hypothesis of MIC creep in a multicentre study, testing all the isolates concurrently. METHODS Nineteen laboratories in the UK and Ireland contributed isolates from blood to the BSAC Bacteraemia Resistance Surveillance Programme every year between 2001 and 2007. MICs for 271 MRSA from these sites were re-measured at a single central laboratory during a single week by the BSAC agar dilution method, but with √2-fold instead of conventional 2-fold dilutions. Re-test results were compared with the original results obtained each year at the same central laboratory. RESULTS The re-test results were much less variable than the original results and avoided the confounding of experimental variation with year of collection. They demonstrated statistically significant but very slow downward trends in MICs of vancomycin and teicoplanin, at 0.027 and 0.055 doubling dilutions/year, respectively. The original results had suggested more rapid trends in MICs, upward for vancomycin and downward for teicoplanin. The proportion of EMRSA-16 fell from 21% to 9% over the study period, while EMRSA-15 rose from 76% to 85%. CONCLUSIONS Historical data can give a misleading impression of trends in MIC values because of experimental variation between tests conducted at different times. There was no upward creep in glycopeptide MICs for MRSA in the UK and Ireland between 2001 and 2007.

Antimicrobial resistance in the UK and Ireland

After the dramatic expansion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella in the UK and Ireland from 2001 onwards, the situation appears to have stabilized, with similar ESBL prevalence detected in 2007 as in 2006. Equally dramatic, but more welcome, is the sharp reduction since 2005 in the number of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemias in England, and the reduction in prevalence of MRSA as a proportion of all S. aureus bacteraemias. These two trends dominate the information from the major resistance surveillance schemes in the UK and Ireland, but a wealth of further detail is available from these rich information sources. Resistance rates vary between hospitals, between specialities within hospitals and between patients within specialities depending on their characteristics such as age. In addition, resistance varies over time as new genetic mechanisms appear in clinically relevant bacteria, and spread or retreat under the pressures of competition and changing patterns of antibiotic use. Up-to-date information is required, not only at a national level for research and policy purposes, but at a very local level to inform day-to-day clinical decisions.

Bacterial Strain-to-Strain Variation in Pharmacodynamic Index Magnitude, a Hitherto Unconsidered Factor in Establishing Antibiotic Clinical Breakpoints

ABSTRACT Antibiotic pharmacodynamic modeling allows variations in pathogen susceptibility and human pharmacokinetics to be accounted for when considering antibiotic doses, potential bacterial pathogen targets for therapy, and clinical susceptibility breakpoints. Variation in the pharmacodynamic index (area-under-the-concentration curve to 24 h [AUC24]/MIC; maximum serum concentration of drug in the serum/MIC; time the serum concentration remains higher than the MIC [T > MIC]) is not usually considered. In an in vitro pharmacokinetic model of infection using a dose-ranging design, we established the relationship between AUC24/MIC and the antibacterial effect for moxifloxacin against 10 strains of Staphylococcus aureus. The distributions of AUC24/MIC targets for 24-h bacteriostatic effect and 1-log, 2-log, and 3-log drops in bacterial counts were used to calculate potential clinical breakpoint values, and these were compared with those obtained by the more conventional approach of taking a single AUC24/MIC target. Consideration of the AUC24/MIC as a distribution rather than a single value resulted in a lower clinical breakpoint.